The present invention generally relates to metal mesoporphyrin halide compounds and processes for their preparation. More specifically, it relates to processes for making novel intermediate compounds, which can be converted to such mesoporphyrin halide compounds.
Tin (IV) mesoporphyrin IX dichloride or stannsoporfin is a chemical compound having the structure indicated in FIG. 1. It has been proposed for use, for example, as medicament in the treatment of various diseases including, for example, psoriasis (U.S. Pat. No. 4,782,049 to Kappas et al.) and infant jaundice (for example, in U.S. Pat. Nos. 4,684,637, 4,657,902 and 4,692,440). Stannsoporfin is also known to inhibit heme metabolism in mammals, to control the rate of tryptophan metabolism in mammals, and to increase the rate at which heme is excreted by mammals (U.S. Pat. Nos. 4,657,902 and 4,692,400 both to Kappas et al.).
Processes for obtaining stannsoporfin are known in the art. Protoporphyrin IX iron (III) chloride or hemin, of the structural formula indicated in FIG. 2, is commonly used as starting material. The hemin is generally hydrogenated to form an intermediate mesoporphyrin IX dihydrochloride, which is subsequently subjected to tin insertion, yielding stannsoporfin.
One prior method for the preparation of the intermediate mesoporphyrin IX dihydrochloride has involved catalytic hydrogenation of hemin over Pd(0) in formic acid at elevated temperature. Column chromatography of the resulting intermediate obtained by such a method yields an intermediate mesoporphyrin IX dihydrochloride product that reportedly contains about 15% of an unidentified impurity. Another preparation method for this intermediate has been typically performed at lower temperatures with heating hemin in formic acid in the presence of palladium catalyst. This process is reported to reduce the amount of the unidentified impurity; however, the reaction is difficult to drive to completion without decomposition of the intermediate product.
The above referenced methods for the preparation of the mesoporphyrin IX intermediate are used to produce only small, gram scale quantities of the product, and the product further requires subsequent isolation and purification, generally by preparative or column chromatography. Additionally, those methods in which hydrogenation is carried out at lower temperatures yield incomplete reactions, and when higher temperatures are used, degradation of the intermediate product is observed. Consequently, the crude intermediate product requires purification. Furthermore, the above referenced procedures require exceedingly high solvent volumes, thus making the process unsuitable for industrial scale up, since isolation of mesoporphyrin IX dihydrochloride or its free base is performed using a filtration process. Such filtrations and subsequent washings of the products are time-consuming, making the large-scale isolations costly and difficult. Additionally, the limited stability of mesoporphyrin IX in hydrochloric acid at the elevated temperatures required to form the dihydrochloride also complicates the industrial scale up of this process.
The insertion of various metals into porphyrin rings has been described by Fischer and Neumann (Ann. Chem. (1932), 494, 225). The reaction for the insertion of tin is performed in an acid, typically acetic acid, and further typically under reflux, using Sn (II) in the presence of an oxidant. A modified process is also described by Fuhrhop and Smith, as reported in “Porphyrins and Metalloporphyrins” p. 757, Elsevier, Amsterdam, 1975, to include sodium acetate, which buffers the solution and enhances deprotonation of the porphyrin. In most cases, the metal mesoporphyrin halide product crystallizes directly from the reaction mixture on cooling. Such crystallization may be enhanced by the addition of water or methanol.